Br. J. clin. Pharmac.

(1980), 9, 359-364

COMBINATION OF AMINOPHYLLINE
(PHYLLOCONTIN CONTINUS TABLETS) AND SALBUTAMOL IN
THE MANAGEMENT
OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
C.J. CLARK & G. BOYD
Centre for Respiratory Investigation, Glasgow Royal Infirmary,
82 Castle Street, Glasgow G4 OSF

1 The effect of a controlled release theophylline derivative (Phyllocontin Continus tablets) and an
adrenoceptor agonist (salbutamol) was compared when taken singly and concomitantly in twenty
patients with chronic bronchitis and additional reversible airways obstruction using a double-blind
crossover technique.
2 The pulmonary function data showed a significant improvement in airways obstruction with an
associated reduction in hyperinflation on combination therapy, as compared with either drug taken
alone.
3 No significant improvement in patient symptoms occurred on combination therapy as compared
with either drug taken alone.
4 A high incidence of side-effects was noted with both Phyllocontin Continus and salbutamol.
Combination therapy, however, did not increase the frequency or severity of side-effects seen on
either drug alone.
5 Although a proportion of patients showed evidence of intercurrent infection during the nine-week
trial period, this did not appear to influence the results for the group as a whole.

Introduction
Both f,-adrenoceptor agonists and methylxanthines
have been shown to cause bronchodilation by
increasing levels of cyclic AMP which appears to
regulate bronchodilation and immune mediator
release in lung (Orange, Kaliner, Laraia & Auster,
1971). Their modes of action are, however, thought to
be different, the former stimulating the adenyl cyclase
system and the methylxanthines inhibiting cyclic
nucleotide phosphodiesterase. It has been demon-
strated in vivo in the inotropic response of rabbit atria
(Rall & West, 1963) and in human lung (Kaliner,
Orange, Koopman Austen & Laraia, 1971), that these
two classes of drug act synergistically in raising cyclic
AMP concentrations.
Salbutamol is a f2-adrenoceptor agonist that is
relatively free from cardiac effects (Lands, Luduena
& Buzzo, 1967; Cullum, Farmer, Jack & Levy, 1969)
and is commonly used both orally and as a
pressurized aerosol in the treatment of reversible
airways obstruction.
Theophylline rendered soluble as its ethylene
diamine complex (aminophylline) has long been used
intravenously, orally and rectally in the prevention
and relaxation of bronchospasm. Oral aminophylline
has required frequent administration to maintain
0306-5251/80/040359-06 $01.00
therapeutic levels on account of the short half life of
the drug and has caused distressing irritation of the
gastric mucosa in some patients. The recent
introduction of a controlled release aminophylline
preparation (Phyllocontin Continus Tablets PC) has
enabled maintenance of therapeutic theophylline
levels on a twice daily dosage and has been reported
(Boroda, Miller, Leslie, Nicol & Thomson, 1973) to
reduce the incidence of gastric irritation. The aim of
the present study was to evaluate the use of a
controlled release aminophylline tablet (PC) as a
concomitant therapy in patients receiving salbutamol
and to determine if the synergism which has been
demonstrated in relation to cyclic 3,5-AMP
concentrations, is of clinical benefit.
Methods
The forty patients initially selected for the trial
fulfilled The Medical Research Council criteria for
the diagnosis of chronic bronchitis (chronic or
recurrent cough productive of sputum, occurring on
most days for at least 3 months of the year and for 3
or more successive years) and showed demonstrable
© Macmillan Journals Ltd 1980
360 C.J. CLARK & G. BOYD

reversibility of airways obstruction with at least 15%
improvement in forced expired volume in 1 s (FEV1)
after a single dose of isoprenaline by aerosol on at
least two occasions prior to inclusion in the trial.
Those with current pulmonary infection, history of
pulmonary tuberculosis, chronic renal failure, cor
pulmonale, left ventricular failure, systemic hyper-
tension or ischaemic heart disease, were excluded
from consideration. Twenty patients completed the
trial, twelve male and eight female, their ages ranging
from 31 to 69 years (mean 51 years). All other
bronchodilator therapy was discontinued and in one
patient on low dose steroid therapy, this was
continued unchanged throughout the trial period.
There were three phases of treatment. In Phase I
each subject received PC one tablet (225 mg) twice
daily for 1 week, then two tablets twice daily for a
further 7 days. In Phase II the patients continued with
either active PC tablets two twice daily or an identical
placebo tablet two twice daily for 3 weeks, with in
addition, salbutamol 4 mg three times daily during
this period. In Phase III, the PC was changed to
placebo or vice versa depending on the regime given
in Phase II, one tablet twice daily for 1 week followed
by two twice daily for a further 3 weeks with in
addition, salbutamol 4 mg three times daily during
this period. There were four visits in all including the
pre-trial interview, which consisted of a clinical
assessment and the measurement of pulmonary
function tests. Symptoms of cough, sputum
production and exertional dyspnoea, were recorded
and graded into one of three categories according to
severity. Questions relating to intercurrent chest
infection were incorporated in the questionnaire and
patients were asked to record any side effects which
they experienced. Recordings of pulse and blood
pressure were taken at completion of the interview on
each occasion. Further assessment of symptoms was
obtained from a daily diary kept by the patients in
which symptoms of cough, wheeze or chest tightness
were graded into one of five categories.
Pulmonary function tests consisted of standard
spirometry using a low inertia spirometer and a
'pulmatest' (PK' Morgan Limited, London) from
which values for vital capacity (VC), FEV1,
functional residual capacity (FRC), residual volume
(RV) and total lung capacity (TLC) were obtained.
Flow volume measurements were completed on each
patient with flow rates compared at constant lung
volume. Maximum expiratory flow was measured at
60% of total lung capacity. Results were expressed in
litres and all volumes were corrected to body
temperature and pressure saturated with water
vapour. The patients were also asked to record in the
daily diary, morning and evening peak flow
estimations using a miniwright peak flowmeter
(AIRMED, London).
Blood samples were taken at each visit for
serological monitoring of antibody titres to common
respiratory viruses, including influenza A, B and C,
parainfluenza 1, 2 and 3, adenovirus, respiratory
syncytial virus, and mycoplasma pneumoniae.

Table 1 Mean values for pulmonary function data + 2 s.d. from the mean before and during trial period. Volumes expressed
in litres (BTPS) and also as a percentage of the mean predicted normal.
Pulmonary Pretreatment Phyllocontin Salbutamoll Salbutamoll
function measurements placebo Phyllocontin
Vital capacity
absolute 3.2 + 0.9 3.4+ 1.0 3.3 + 1.0 3.5 + 1.0
% predicted 74.0+ 16.8 77.7+ 16.9 75.9+ 18.7 79.3+ 16.9
FEV1
absolute 1.8 + 0.9 1.9 + 0.9 1.8 + 0.9 2.0+ 1.0
% predicted 55.3 + 21.8 59.6 + 25.1 55.9 + 22.5 60.8 + 23.9
FEV1/FVC ratio 54.8+ 14.4 54.1 + 15.6 53.9+ 15.2 58.3+ 16.9
Functional residual
capacity (FRC)
absolute 3.8 + 1.2 3.8 + 1.0 4.3 + 1.1 3.9 + 1.1
% predicted 122 +39.0 120 +22.0 136 +33.0 124 +25.0
RV/TLC ratio 46.8+13.7 42.9+12.0 47.8+14.3 45.0+ 11.9
Maximum expiratory
flow rate (60% TLC) 0.8+ 1.3 0.6+ 0.8 0.7+ 0.9
Peak flow 3.3+ 1.4 3.4+ 1.5 3.6+ 1.8
Daily peak flow
(AIRMED) 4.6+ 2.6 5.1 + 3.7 5.2+ 3.7
 COMBINATION OF PC TABLETS AND SALBUTAMOL 361

Analysis of the numerical data was by paired t-tests Symptoms

and evaluation of the symptomatic data was by the
chi-squared test.
Results
Lung function tests
The results of pulmonary function tests are
summarized in Table 1. No significant improvement
in airways obstruction occurred, between baseline
pre-study lung function data and the periods of the
trial in which salbutamol or PL tablets alone were
used, apart from an increase in VC of 200 ml
(P < 0.05) and fall in RV/TLCs of 3.9 (P < 0.02)
on PC tablets compared with salbutamol alone.
However, a significant improvement in airways
obstruction occurred with combination therapy as
compared with pre-study baseline estimations. FEV,
increased by 200 ml (P < 0.05), mean FEV1
(expressed as a percentage of predicted normal) by
5% (P < 0.01) with an increase in the VC (expressed
as a percentage of predicted normal) of 5.3%
(P < 0.01). The FEV1/FVC ratio also rose but this
change was not statistically significant.
Improvement in airways obstruction was seen on
PC therapy alone as compared with salbutamol alone
and although marginal, this was present throughout,
and reached statistical significance with an increase in
FEV1 (expressed as a percentage of predicted normal)
of 3.7 (P < 0.05), reduction in FRC of 500 ml
(P < 0.01) and 15% of mean predicted normal
(P < 0.02), with a reduction RV/TLC ratio of 4.9%
(P < 0.01).
Historical data is summarized in Tables 2 and 3. No
significant alteration of cough, sputum production,
dyspnoea, or severity of chest complaints was seen on
analysis of the physician's questionnaire and similarly
examination of the patients' diaries showed no
significant change in symptoms of cough, wheeze and
chest tightness throughout the different phases of
treatment.
Respiratory infection
Nine patients reported chest infections of which, one
was related to rising titres to Influenza A, one to
parainfluenza 3, and 2 to respiratory syncytial virus.
Two other individuals had rising viral titres
(influenza A, parainfluenza 3) suggestive of infection
without clinical symptoms. However, eighteen out of
twenty patients had elevated viral titres indicating
previous exposure to the respiratory viral pathogens.
When the data was re-examined after removing those
eleven individuals with documented evidence of
intercurrent infection, analysis of FEV1 expressed as a
percentage of mean predicted normal value and
FEVI/FVC ratio of the remaining subjects, showed a
similar pattern to those obtained with the group as a
whole.
Side effects
The incidence of side effects is shown in Table 4. A
significant incidence of side effects was seen with both
salbutamol and PC, 24% (7 out of 29) of those
receiving salbutamol reported tremor, and 50% (18

Table 2 Physician questionnaire

Assessment Severity Pre-treatment Phyllocontin Salbutamoll Salbutamoll x2 p
placebo Phyllocontin
Chest Poor 4 4 2 1
Moderate 12 11 11 12 3.72 0.5
Good 4 5 7 7
Cough Absent 2 2 3 3
Occasional 12 10 9 11 1.45 0.95
Frequent 6 8 8 6
Sputum Less than normal 0 5 5 8
Normal 18 13 12 11 10.48 0.1
More than nonnal 2 2 3 1
Exertional Absent 1 1 2 3
dyspnoea Occasional 7 6 12 13 12.18 0.05
Frequent 12 13 6 4
362 C.J. CLARK & G. BOYD

out of 36) receiving PC reported side effects, of whom Discussion

twelve suffered nausea, five heartburn and abdominal
discomfort, two headaches and three non-specific
symptoms. Overall, however, these side effects were
severe enough to warrant withdrawal of the drug in
only five patients (13%).
Reasons for withdrawal
Of the twenty patients who failed to complete the
trial, five had intercurrent illness, seven complained
of side effects of the trial tablets, four were reluctant
to continue the required lung function tests, and four
defaulted with no reason given.
The present study examined the bronchodilator effect
of PC tablets, 450 mg twice daily, and salbutamol,
4 mg three times daily, as oral preparations both
separately and in combination, using a double-blind
crossover technique over a 9-week period. These
dosages were chosen since they were the maximum
recommended to produce therapeutic benefit without
the occurrence of troublesome side effects. The
combination of PC tablets with oral salbutamol
produced significantly greater bronchodilation and
reduction in hyperinflation than either preparation

Table 3 Patient diary data

Assessment Severity Phyllocontin Salbutamoll Salbutamoll 12 p
plac ebo Phyllocontin
Wheeze None 6 9 10
Slight 6 3 2
5.69 NS
Moderate 7 6 8
Severe 1 2 0
Cough None 3 5 5
Slight 11 9 7
3.50 NS
Moderate 6 6 7
Severe 0 0 1
Chest tightness None 9 8 8
Slight 5 6 7
3.50 NS
Moderate 6 5 4
Severe 0 1 1

Table 4 Incidence of side effects attributed to salbutamol and

Phyllocontin in the forty patients initially participating in the study.
Drug Side effec t Incidence %
Salbutamol Tremor 7 out of 29* 240%
Phyllocontin 18 out of 36t 50%
Nausea 12
Heartburn and
Abdominal discomfort 5
Headaches 2
Non-specific complaints
e.g. 'not feeling well' 3
* 11
patients discontinued the trial before completing a period on
salbutamol therapy.
t4 patients defaulted.
 COMBINATION OF PC TABLETS AND SALBUTAMOL
used alone. This observation is similar to that
reported by workers using other /3-adrenergic
receptor agents in combination with methylxanthine
derivatives (Smith, Kuo & Steen, 1976; Dyson &
Campbell, 1977; Marlin, Hartnett, Berand & Hacket,
1978; Wolfe, Tashkim, Calvanese & Simmons, 1978)
and the improvements in pulmonary function which
were noted were indicative of an additive rather than
a synergistic effect (Marlin et al., 1978). In the present
study, the use of PC tablets with oral salbutamol
produced no clinical evidence of haemodynamic
disturbance, nor any indication of added toxicity so
that patients free from side effects with either drug
alone may readily tolerate the combined regime and
may, thereby, achieve more effective bronchodilation.
Despite the clear cut improvement in bronchodilation
which was noted when the drugs were used together,
no subjective improvement in clinical well-being was
recorded by the patients during the course of this
study. It has been suggested (Wolfe et al., 1978) that
the additive effect noted between these two groups of
bronchodilators may permit the use of both drugs in
high dosage in subjects where less than adequate
bronchodilation was obtained with a high dose of
either drug used alone or lower doses may be
employed in order to achieve the same degree of
bronchodilation but without the risk of side effects
which are prevalent at higher doses. It is clear,
therefore, that longer term studies would be required
to evaluate more completely the extent of the
therapeutic advantages when employing com-
binations of these two classes of oral bronchodilator
agents in the management of chronic reversible
airways obstruction.
The high incidence of side effects found with
Phyllocontin Continus tablets in this study, mainly of
nausea, heartburn and abdominal discomfort, was
similar to that noted by Greening and his co-workers
(Greening, Baillie, Gribbon & Pride, 1979) but in
contrast to other reports (Boroda et al., 1973;
References
ACHARIYA, A.B. (1977). The role of oral bronchodilator
drugs in an acute chest unit. Pharmatherapeutica 1,
373-377.
BORODA, C., MILLER, R.B., LESLIE, S.T., NICOL, E.G. &
THOMSON, I. (1973). Comparison of the bioavailability
of aminophylline in a conventional base and in a
continuous-release base. J. clin. Pharmac., 13, 383.
BOWMAN, W.C. & KNOTT, M.W. (1969). Actions of
sympathomimetic amines and their antagonists on
skeletal muscle. Pharmac. Rev., 21, 27-72.
CHANG, K. C., BELL, T.D., LAUER, B.A. & CHAI, H. (1978).
Altered theophylline pharmacokinetics during acute
respiratory viral illness. Lancet, i, 1132.
363
Dhatariya, 1975; Maneksha, 1976; Achariya, 1977)
in which toxicity was noted to be minimal and
gastrointestinal disturbance rare. The explanation for
this difference is not clear. A recent review of the
factors which affect theophylline clearance (Ogilvie,
1978) implicated increasing age, obesity, smoking and
liver dysfunction as important elements which
decrease the clearance of this drug and, therefore,
which may increase the potential for developing
toxicity. In the present study, however, these
population characteristics do not appear biased in the
direction of reduced theophylline clearance and
cannot, therefore, account for the high prevalence of
side effects which was observed.
Serological monitoring of antibodies to commom
respiratory viruses confirmed that a significant
number of patients developed respiratory infections
during the 9 weeks of the trial period. When the
pulmonary function data from those who suffered an
infective incident during this time were analysed, they
were identical to the data from the group as a whole.
So that the overall pattern of pulmonary function
throughout the study was not significantly affected by
intercurrent infection. It has been suggested,
however, that acute viral infective incidents can
reduce the clearance of theophylline (Chang, Bell,
Lauer & Chai, 1978; Fleetham, Nakatsu & Munt,
1978) so that toxic effects may emerge in these
situations. During the course of this work, eleven of
the twenty subjects had evidence of recent respiratory
infections and eighteen of the total group had
elevated viral titres consistent with infection in the
recent past. It may be that the relatively high
incidence of infection within the series accounted for
the increased prevalence of side effects which was
noted.
We are most grateful to Dr R.G. Sommerville, Consultant
Virologist, Belvidere Hospital, for his assistance in
monitoring the viral serology during this study.
CULLUM, V.A., FARMER, J.B., JACK, D. & LEVY G.P. (1969).
Salbutamol, a new selective /3-adrenoceptive receptor
stimulant. Br. J. Pharmac., 35, 141.
DHATARIYA, R.C. (1975). A trial of Phyllocontin (Slow
Aminophylline) tablets in patients with bronchospasm.
J. int. med. Res., 3, 236-240.
DYSON, A.J. & CAMPBELL, I.A., (1977). Interaction between
choline theophyllinate and salmefamol in patients with
reversible airways obstruction. Br. J. clin. Pharmac. 4,
677-682.
FLEETHAM, J.A., NAKATSU, K. & MUNT, P.W. (1978).
Theophylline pharmacokinetics and respiratory
infections. Lancet, ii, 898.
364 C.J. CLARK & G. BOYD
GREENING, A.P., BAILLIE, E., GRIBBIN, H.R. & PRIDE N.B.
(1979). A double-blind trial of oral aminophylline
(Phyllocontin Continus tablets) in airflow obstruction:
preliminary communication. J. int. med. Res., 7, 47.
KALINER, M.A., ORANGE, R.P., KOOPMAN, W.J., AUSTEN,
K.F. & LARAIA, P.J. (1971). Cyclic adenosine 3',5'-
monophosphate in human lung, Biochem. Biophys. Acta,
252, 160-164.
LANDS, A.M., LUDUENA, F.P. & BUZZO, H.J. (1967).
Differentiation of receptors responsive to isoproterenol.
Life Sci., 6, 2241.
MANEKSHA, S. (1976). A comparative crossover study of
two long-acting bronchodilator preparations. Curr. med.
Res. Opin., 4, 207-211.
MARLIN, G.E., HARTNETT, B.J.S., BEREND, N. & HACKET,
N.B. (1978). Assessment of combined oral theophylline
and inhaled f,-adrenoceptor agonist bronchodilator
therapy. Br. J. clin. Pharma., 5, 45-50.
OGILVIE, R.I. (1978). Clinical pharmacokinetics of theo-
phylline. Clin. Pharmacokin., 3, 267-293.
ORANGE, R.P., KALINER, M.A., LARAIA, P.J. & AUSTEN,
K.F. (1971). Immunological release of histamine and
slow reacting substance of anaphylaxis from human
lung. II Influence of cellular levels of cyclic AMP. Fed.
Proc., 30, 1725-1729.
RALL, T.W. & WEST, T.C. (1963). The potentiation of cardiac
inotropic responses to norepinephrine by theophylline.
J. Pharmac. exp. Ther., 139, 269-274.
SMITH, R., KUO, J. & STEEN, S.N. (1976). Metaproterenol
with and without theophylline in bronchospastic disease.
IRCS Med. Sci., 4, 562.
WOLFE, J.D.,TASHKIN, D.P., CALVARESE, B. & SIMMONS,
M. (1978). Bronchodilator effects of terbutaline and
aminophylline alone and in combination in asthmatic
patients. New Engl. J. Med., 298, 363-367.
(Received June 6, 1979)